Nanocarrier-mediated targeting of chemotherapy-induced DPP4 enhances T cell infiltration and improves cancer immunochemotherapy.

Cancer immunotherapy has transformed cancer treatment, yet its efficacy remains limited by a "cold" tumor immune microenvironment (TIME) characterized by poor T cell infiltration. Induction of immunogenic cell death (ICD) improves T cell infiltration by promoting the release of T-cell-recruiting chemokines such as CXCL10. However, the outcome may be limited by dipeptidyl peptidase IV (DPP4), a serine protease that degrades CXCL10 and related chemokines. We report that chemotherapeutic agents, particularly those capable of inducing strong ICD, transcriptionally upregulate DPP4 in cancer cells, establishing a negative feedback mechanism that dampens CXCL10-mediated immune responses. To overcome this limitation, we developed an enhanced triple-combination immunochemotherapy based on the codelivery of doxorubicin, a DPP4 inhibitor (Sitagliptin, Sitag), and a COX-2 inhibitor (5-ASA) using a 5-ASA-derivatized hyaluronic acid (HA) dendrimer nanocarrier (HASA). HA is a natural ligand for CD44 that is overexpressed on tumor and tumor endothelial cells, enabling precise targeting. In preclinical tumor models, this strategy enhanced T cell infiltration, antitumor immunity, and therapeutic efficacy while minimizing systemic toxicity, resulting in significant survival benefit when combined with anti-PD-1 therapy. Our work identifies chemotherapy-induced DPP4 upregulation as an adaptive immune-resistance feedback loop and establishes a targeted triple-drug nanoplatform that integrates chemotherapy, DPP4 inhibition, and COX-pathway modulation for enhanced immunochemotherapy.